Soy Isoflavones: Good or Bad?

Research studies have indicated that plasma concentrations of the soy isoflavones daidzein and genistein reach their highest peak six hours after intake, preceded by a smaller initial peak one-hour post-meal (Franke, Lai & Halm, 2014).

The initial peak reflects isoflavone absorption in the small intestine after its transformation into an aglycones, while the second peak corresponds the aglycone being absorbed in the colon. Hence, the gut microbiome influences the biological effects of isoflavones.

If the gut bacteria are diverse and functioning, the aglycone is transformed into equol, a metabolite that has greater estrogenic activity (Setchell & Clerici 2010). Equol appears in plasma about eight hours after isoflavone intake owing to the transit time of daidzein to the colon and its subsequent conversion to equol by the microbiota. Studies measuring urinary equol excretion after soy consumption indicated that equol was produced by about 25%-30% of the adult population in Western countries compared to 50%-60% of adults living in Asian countries and Western adult vegetarians (Setchell & Cole, 2006). 

Soy isoflavones have weak oestrogenic or hormone-like activity due to their structural similarity with 17-beta-estradiol.

What are oestrogens?

Oestrogens are signalling molecules that exert their effects by binding to oestrogen receptors within cells. Soy isoflavones can preferentially bind to oestrogen receptor-beta (ER-Beta) — rather than ER-alpha — mimicking the effects of oestrogen in some tissues and blocking the effects of estrogen in others. This anti-oestrogenic effect in reproductive tissue could help reduce the risk of hormone-associated cancers (breast, uterine, and prostate), while oestrogenic effects in other tissues could help maintain bone mineral density and improve blood lipid profiles. Furthermore, soy isoflavones have also been found to inhibit tyrosine kinases (Akiyama, Ishida, Nakagawa Ogawara, Watanabe & Itoh 1987) enzymes that play critical roles in the signalling pathways that stimulate cell proliferation. 

High isoflavone intake from soy foods in Asian countries (average range, 25 to 50 mg/day) has been shown to reducing the risk of breast cancer; in contrast, the incidence of breast cancer remains elevated in Europe, North America, and Australia/New Zealand (Torre, Bray, Siegel Ferlay, Lortet-Tieulent & Jemal 2015) where average isoflavone intakes in non-Asian women are generally less than 2 mg/day. In a meta-analysis of one prospective cohort study and seven case-control studies conducted in Asian populations and in Asian Americans, higher versus lower intakes of dietary soy isoflavones (≥20 mg/day vs. ≤5 mg/day) were found to be associated with a 29% reduced risk of breast cancer (Wu, Yu, Tseng, & Pike 2008). This would explain why moderate versus low intakes of isoflavones (10.8 mg/day vs. 0.23 mg/day; cohort followed for a median of 7.4 years) during adulthood was not associated with a reduced risk of breast cancer in British women enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) study (Travis, Allen, Appleby, Spencer, Roddam & Key 2008).

Incidence rates of prostate cancer are much higher in Northern America, Northern and Western Europe, Australia, and New Zealand compared to Asian countries, such as Japan and China, where isoflavone-rich soybeans are common components of the diet (Torre et al., 2015). Soy food consumption has been associated with a reduced risk of prostate cancer in recent pooled analyses of observational studies (Zhang, Wang, Chen Yin & Song 2016). 
Interesting results have also emerged from studies conducted in different ethnic populations on bone density after prolonged consumption of soy isoflavone.  Compared to Caucasian women, the incidence of hip fractures tends to be lower among Asian women who are habitual soy food consumers (Silverman & Madison, 1988). Decreased incidence of hip fracture in Hispanics, Asians, and blacks: California Hospital Discharge Data. American journal of public health, 78(11), 1482-3.), suggesting that long-term soy food consumption might protect against bone loss or osteoporotic fracture. 

The prolonged consumption of isoflavones has also been associated with a reduced risk of stroke. In the Japan Public Health Center-based Study (mean follow-up, 13.5 years), consumption of soy foods was associated with a reduced risk of stroke in Japanese women (ages, 40 to 59 years) — but not in men. In this cohort, the highest versus lowest quintile of soy isoflavone intakes was found to be associated with a 65% lower risk of ischaemic stroke and a 63% lower risk of myocardial infarction in women (Kokubo, Iso, Ishihara, Okada, Inoue & Tsugane 2007).
Several intervention studies have examined soy intake in relation to several cardiometabolic risk factors. A recent meta-analysis of randomized controlled trials concluded that intake of either soy products (i.e., whole soybeans, soy milk, nuts, oil, and flour), soy protein isolate, or soy isoflavones for one month to one year could significantly improve serum lipid profiles in healthy and hypercholesterolemic individuals by lowering circulating triglycerides, total cholesterol, and LDL-cholesterol (Tokede Onabanjo Yansane Gaziano & Djousse, 2015). A meta-analysis of 14 randomized controlled studies reported a reduction in circulating C-reactive protein (CRP) — an inflammation marker associated with increased cardiovascular risk — following soy isoflavone intake in postmenopausal women with elevated baseline CRP concentrations (>2.2 mg/L). The preservation of normal arterial function plays an important role in cardiovascular disease prevention. The ability of all types of blood vessels, including arteries, to dilate in response to nitric oxide (NO) produced by the endothelial cells that line their inner surface is compromised in people at high risk for cardiovascular disease (Landmesser, Hornig & Drexler 2004). 

Food sources
Isoflavones are found in small amounts in several legumes, grains, and vegetables, but soybeans are by far the most concentrated source of isoflavones in the human diet.

Average dietary isoflavone intakes in Japan, China, and other Asian countries range from 25 to 50 mg/day. Dietary isoflavone intakes are considerably lower in Western countries. Twenty-four-hour dietary recall data collected from 36,037 individuals in 10 countries (participating in the EPIC study) showed average isoflavone intakes to be lower than 1 mg/day. Compared to other European countries, the isoflavone intake was slightly higher in the British general population (2.3 mg/day) and health-conscious cohort (19.4 mg/day) (Zamora-Ros, Knaze & Lujan-Barroso 2012). Traditional Asian foods made from soybeans include tofu, tempeh, miso, and natto. Soy products that are gaining popularity in Western countries include soy-based meat substitutes, soy milk, soy cheese, and soy yoghurt. The isoflavone content of a soy protein isolate depends on the method used to isolate it. Soy protein isolates prepared by an ethanol wash process generally lose most of their associated isoflavones, while those prepared by aqueous wash processes tend to retain them.